2. Academic Validation
  3. Structure-activity relationship and biological evaluation of xanthine derivatives as PCSK9 inhibitors for the treatment of atherosclerosis

Structure-activity relationship and biological evaluation of xanthine derivatives as PCSK9 inhibitors for the treatment of atherosclerosis

  • Eur J Med Chem. 2022 Dec 26;247:115047. doi: 10.1016/j.ejmech.2022.115047.
Meng-Qian Qiao 1,  Yue Li 1,  Yu-Xin Yang 1,  Chen-Xu Pang 1,  Yi-Ting Liu 1,  Cong Bian 1,  Li Wang 2,  Xiao-Fang Chen 3,  Bin Hong 4
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing, 100050, China.
  • 2 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing, 100050, China. Electronic address: wangli_imb@163.com.
  • 3 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing, 100050, China. Electronic address: chenxiaofang@imb.pumc.edu.cn.
  • 4 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing, 100050, China. Electronic address: binhong69@hotmail.com.
PMID: 36586297 DOI: 10.1016/j.ejmech.2022.115047
Abstract

Developing non-statin small molecules for the treatment of hypercholesterolemia remains challenging. The proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapies have attracted considerable attentions. Forty-five 7030B-C5 derivatives were synthesized and evaluated for the PCSK9 repression activity, taking the PCSK9 transcriptional inhibitor 7030B-C5 as the lead. Structure-activity relationship (SAR) analysis at C8 and N7-position was carried out, and compound 3s and 5r exhibited comparable PCSK9 transcriptional inhibitory activity but much lower cytotoxicity with the therapeutic index (TI) values doubled of that of 7030B-C5. In the in vitro assay, both compounds significantly reduced the level of PCSK9 protein and increased LDL receptor (LDLR) protein level. What's more, both compounds promoted LDL Cholesterol (LDL-C) clearance more efficiently than 7030B-C5 in HepG2 cells. Most importantly, compound 3s reduced the atherosclerotic plaque areas with promising lipid-lowing effects in apoE KO mice with a higher in vivo activity and lower toxicity. The regulatory mechanism of 3s was explored that it might target the transcription factor HNF1α and/or HINFP upstream of PCSK9 transcription, similar to that of 7030B-C5. Thus, 3s was considered as a potential anti-atherosclerosis drug candidate as a novel PCSK9 down-regulatory agent, worthy of further investigations.

Keywords

Atherosclerosis; Cholesterol; PCSK9; Structure–activity relationship; Transcriptional inhibition.

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